EP1045698B1 - Vaccin specifique de patient contre les tumeurs malignes des leucocytes elabore a partir de proteoliposomes a membrane - Google Patents

Vaccin specifique de patient contre les tumeurs malignes des leucocytes elabore a partir de proteoliposomes a membrane Download PDF

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EP1045698B1
EP1045698B1 EP99900822A EP99900822A EP1045698B1 EP 1045698 B1 EP1045698 B1 EP 1045698B1 EP 99900822 A EP99900822 A EP 99900822A EP 99900822 A EP99900822 A EP 99900822A EP 1045698 B1 EP1045698 B1 EP 1045698B1
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membrane
vaccine
liposome according
white blood
lipid
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EP1045698A1 (fr
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Mircea C. Popescu
Lawrence Boni
Richard J. Robb
Michael M. Batenjany
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Biomira USA Inc
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Biomira USA Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A61K2039/55533—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/5555—Muramyl dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A

Definitions

  • the present invention is directed to the production of novel compositions, useful as vaccines for treating white blood cell (WBC) malignancies.
  • WBC white blood cell
  • the invention relates to a liposomal, patient-specific vaccine comprised of WBC membranes that may be formulated by adding other lipids and/or immunostimulators, thereby forming a novel membrane-proteoliposome (MP) structure.
  • MP membrane-proteoliposome
  • Known vaccines typically utilize either purified antigen or attenuated pathogen as the immunogen.
  • attenuated vaccines can actually cause the infection against which a person is being immunized.
  • purified antigens may not induce a long-term immune response and sometimes induce no response at all.
  • presentation of the antigen in the presence of liposomes can induce a long-term response which is essential for any effective vaccine.
  • liposomes may also be formed, at least in part, from cell membranes of malignant cells which contain potential antigens. Due to the presence of membrane associated antigens, these membrane-derived preparations may be used as malignancy-specific vaccines. Indeed, some types of membrane-derived preparations have been used as tumor specific antigens (TSA) to treat melanomas and murine SL2 lymphosarcoma.
  • TSA tumor specific antigens
  • MPs membrane-proteoliposomes
  • MPs are provided which are malignancy-specific, patient-specific and are easily prepared.
  • MPs are provided which comprise the cell membrane of a white blood cell malignancy, at least one immunostimulator and at least one lipid, where the lipid may be added in the form of lipid powder, or preformed liposomes.
  • Another embodiment of the invention provides novel vaccine formulations which comprise an MP comprising the cell membrane of a white blood cell and may include at least one immunostimulator.
  • the inventive methods comprise formulating a vaccine directly from isolated antigen-containing membranes from patients' own white blood cells (WBCs), thus rendering them highly effective and patient-specific.
  • WBCs white blood cells
  • the instant invention provides membrane-proteoliposome structures (MPs) that are useful in formulating patient-specific vaccines for treating white blood cell (WBC) malignancies.
  • MPs membrane-proteoliposome structures
  • proteoliposomal vaccine made of antigen idiotype (1d) and interleukin-2 (IL-2) proteins within a liposomal structure (Popescu, et al., PCT/US97/02351).
  • a novel liposomal structure is disclosed herein, called a membrane-proteoliposome (MP), which usually comprises phospholipid, integral membrane from a malignant WBC and a potent immunostimulator.
  • MP membrane-proteoliposome
  • the present invention is based in part on the discovery that membranes from WBC malignancies can be fused with other components to form an effective vaccine against the malignancy.
  • All WBCs including polymorphonuclear cells (PMN), monocytes and T- or B-lymphocytes, are subject to malignant transformation leading to a spectrum of diseases.
  • PMN polymorphonuclear cells
  • monocytes monocytes
  • T- or B-lymphocytes are subject to malignant transformation leading to a spectrum of diseases.
  • B-cell malignancy includes non-Hodgkin's lymphomas, chronic lymphocytic leukemia and multiple myeloma.
  • the present invention has relevance in treating or preventing many such malignancies.
  • WBC's can be obtained directly from the patient to isolate the intact membranes, rich in tumor-specific antigens (TSA) and tumor-associated antigens (TAA).
  • TSA tumor-specific antigens
  • TAA tumor-associated antigens
  • cells will be enucleated and their plasma membranes separated from other components (e.g., mitochondria, lysosomes).
  • the plasma membranes typically are washed to remove cellular contaminates, which may include cytoskeletal structures, and the separation material.
  • the plasma membrane suspensions may then be exposed to mechanical size reduction, for example, by extrusion, homogenization or other shearing methods. This will allow for filtration through a sterilizing filter.
  • the WBC membranes may also be detergent solubilized, reconstituted with lipids of choice then size reduced.
  • the isolated membranes may be sterilized by, for example, ⁇ -irradiation.
  • the isolated malignant cell membranes alone or in combination with added lipids, can then be used to entrap an immunomodulator.
  • the extent of entrapment of immunomodulator, immunogenicity and efficacy of the MP as a vaccine can be modulated by the nature of the constitutive lipids.
  • a thus optimized MP formulation may then be used to vaccinate the patient against his/her specific WBC malignancy.
  • the present invention is particularly useful in vaccinating against non-Hodgkin's lymphomas.
  • lymphomas are characterized by the expression of monotypic immunoglobulin (Ig) which can serve as a tumor-specific antigen.
  • Ig monotypic immunoglobulin
  • these cells typically express surface molecules involved in antigen presentation, such as class I and class II MHC molecules (with associated TSA or TAA peptide), and costimulation, such as adhesion proteins and B7.1 and B7.2 (CD80 and CD86).
  • class I MHC molecules with associated TSA or TAA peptide
  • costimulation such as adhesion proteins and B7.1 and B7.2 (CD80 and CD86).
  • adhesion proteins and B7.1 and B7.2 CD80 and CD86.
  • the presence of a class I MHC molecule in the inventive formulation will potentially enhance the cytotoxic immune response against the tumor.
  • the present invention provides a proteoliposomal, patient-specific vaccine for WBC malignancies that, in one embodiment, is produced by entrapping a potent immunomodulator together with malignant white blood cell membranes.
  • the resulting membrane-proteoliposome can be either (1) a cell-derived membrane patched with at least one added membrane-forming lipid or (2) a lipid membrane (e.g., a liposome) patched with cell-derived membrane.
  • lipid membrane e.g., a liposome
  • pattern is meant that the resulting MP is non-homogenous with respect to the component lipid sources.
  • contiguous portions of the MP will be essentially WBC membrane-derived, while others will be derived essentially from the added membrane-forming lipids.
  • MP formulations are described which contain membrane from a mouse B-cell lymphoma (38C13), and which were used as effective vaccines in a mouse model of non-Hodgkin's B-cell lymphoma.
  • the vaccine compositions of the invention typically comprise at least one membrane component of a malignant white blood cell.
  • Important membrane components specifically include components involved in immunity.
  • Components involved in immunity can include any macromolecules, such as proteins, lipids and carbohydrates, which are normally an integral part of, or simply associated with, the cell membrane. Other organic and inorganic substances which are similarly associated with the cell membrane also are included.
  • Some preferred components involved in immunity include tumor-specific antigens (TSA), tumor associated antigens (TAA), major histocompatability (MHC) antigens (class I and class II molecules) and costimulatory molecules.
  • Costimulatory molecules are second signal immunostimulators associated with T cell activation.
  • Costimulatory molecules typically are cell surface molecules which act in conjunction with primary immune signals, i.e., antigen presented by MHC molecules, to generate an immune response.
  • primary and secondary signal molecules facilitate antigen presentation by antigen presenting cells (APC) to T cells.
  • APC antigen presenting cells
  • costimulatory molecules include cellular adhesion molecules and CD-40.
  • Specific preferred costimulatory molecules include B7.1, B7.2 and ICAM-1 (CD 56).
  • the membrane component takes the form of an isolated plasma membrane (in whole or in part).
  • the isolated plasma membrane preferably is constituted of lipid which is membrane-forming.
  • all components normally integral to or associated with the cell plasma membrane, including components involved in immunity, typically are present.
  • This preferred membrane component will usually be isolated from a patient sought to be vaccinated.
  • the resultant vaccine comprising this membrane component will be patient-specific and specific for the WBC malignancy from which the membrane component is isolated. It is envisioned that a vaccine formulated with a membrane component from one patient will be useful in vaccinating another patient, given similar antigenic determinants.
  • patient-specific refers to the fact that the vaccine is derived from a particular patient (it thus will be useful in treating that same patient), not that it is useful only to treat the patient or the specific malignancy from which it is derived.
  • patient will normally be human, non-human animals may also be patients.
  • the inventive vaccine compositions can be made specific for any white blood cell malignancy.
  • the clinician will be familiar with the various types of white blood cells and their malignancies.
  • Representative white blood cells include polymorphonuclear cells (PMNs), monocytes, T-lymphocytes and B-lymphocytes.
  • PMNs polymorphonuclear cells
  • monocytes monocytes
  • T-lymphocytes T-lymphocytes
  • B-lymphocytes Some representative white blood cell malignancies include lymphomas, leukemias, and myelomas.
  • Other white blood cell malignancies are known in the art. Further examples of WBC malignancies are found in McCance et al., PATHOPHYSIOLOGY: THE BIOLOGIC BASIS OF DISEASE IN ADULTS AND CHILDREN, chapters 24 and 25, pp. 800-855 (The C.V. Mosby Company 1990).
  • Some preferred vaccine compositions further comprise at least one immunostimulator.
  • Immunostimulators specifically include any substance that can be used to modulate the immune response. Especially useful immunostimulators are those which can be used to stimulate the specific immune response to components involved in immunity. Exemplary classes of such useful immunostimulators include: lymphokines, such as IL-2, IL-4 and IL-6; interferons, such as IFN- ⁇ and IFN- ⁇ ; other cytokines, such as GM-CSF and M-CSF; and adjuvants, such as Lipid A, monophosphoryl lipid A (MPL), or muramyl dipeptide (MDP). Immunostimulators may be used alone or in any combination with one another. Some compositions comprise at least two immunostimulators, such as IL-2 and MPL or MDP, and other combinations of cytokines with adjuvants.
  • lipids other than those present in the cell membrane component i.e., from an exogenous source.
  • exogenous lipids may be from natural or synthetic sources.
  • Preferred lipids include phospholipids, glycolipids, and especially saturated phospholipids.
  • Saturated phospholipids include 1,2-dimyristoylphosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), 1,2-dimyristoylphosphatidylglycerol (DMPG).
  • DMPC 1,2-dimyristoylphosphatidylcholine
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • DMPG 1,2-dimyristoylphosphatidylglycerol
  • Other useful lipids include cholesterol and derivatives thereof. Of course combinations of these and other lipids are also useful.
  • Preparing an inventive vaccine involves first isolating WBC membrane components, free of other cellular components.
  • WBC membrane components free of other cellular components.
  • isolated membranes typically are combined with other lipids and/or immunostimulators to form MPs.
  • liposome-forming methods known in the art and any of these standard methods may be employed in preparing the present MP.
  • MPs can be prepared containing IL-2 as an immunostimulator.
  • the IL-2 is mixed with the WBC membranes and entrapped by freeze/thawing from -70 °C to 37 °C, followed by brief vortexing and short bath sonication (30 seconds).
  • the preparation can include the addition of a suitable lipid powder at 50 to 300 mg/mL (final).
  • MPs can be formed independent of exogenous lipids or from WBC membrane components mixed with exogenous lipids.
  • MPs can also be prepared containing only WBC membrane components, which may be fused with preexisting liposomes which comprise exogenous lipids.
  • a WBC membrane suspension is lyophilized then hydrated with a suitable liquid, for example, water, normal saline solution (NSS) or a suitable buffer.
  • the hydration liquid may contain an immunomodulator.
  • WBC membrane components are formed.
  • MLVs multilamellar vesicles
  • the MLVs may contain a pre-incorporated immunomodulator, in which case the lyophilized preparation is hydrated with a suitable liquid, which may contain at least one immunomodulator.
  • a suitable liquid which may contain at least one immunomodulator.
  • the WBC membrane suspension is size reduced by extrusion, homogenization or other shearing methods to form small unilamellar vesicles (SUVs).
  • the SUVs are then lyophilized and hydrated with a suitable liquid, optionally containing an immunomodulator.
  • SUVs prepared from exogenous lipids also may be added prior to the lyophilization step.
  • the immunomodulator may be mixed with the SUV's prior to lyophilization. In any event, whenever the lyophilized preparation is hydrated, the liquid may contain an immunomodulator.
  • a WBC membrane suspension is added to MLVs comprising exogenous lipids.
  • the resulting mixture is lyophilized and hydrated with water, NSS or buffer followed by size reduction (extrusion, homogenization or other shearing methods) to form SUV's.
  • An immunomodulator may be added and the mixture is allowed to fuse overnight.
  • Another method involves adding a WBC membrane suspension to MLVs comprising exogenous lipids.
  • the mixture is lyophilized and hydrated with a suitable liquid.
  • the resulting suspension is size reduced by extrusion, homogenization or other shearing methods to form SUVs.
  • the SUVs are lyophilized and hydrated with a suitable liquid, optionally containing an immunomodulator.
  • the WBC membrane suspension may be size reduced by extrusion, homogenization or other shearing methods to form SUVs.
  • An immunomodulator is added to the SUVs and the mixture is then allowed to fuse overnight.
  • Vaccines may also be formulated with a pharmaceutically acceptable excipient.
  • excipients are well known in the art, but typically should be physiologically tolerable and inert or enhancing with respect to the vaccine properties of the inventive compositions.
  • an excipient it may be added at any point in formulating the vaccine or it may be admixed with the completed vaccine composition.
  • Vaccines may be formulated for multiple routes of administration. Specifically preferred routes include intramuscular, percutaneous, subcutaneous, or intradermal injection, aerosol, oral or by a combination of these routes, at one time, or in a plurality of unit dosages. Administration of vaccines is well known and ultimately will depend upon the particular formulation and the judgement of the attending physician.
  • Vaccine formulations can be maintained as a suspension, or they may be lyophilized and hydrated later to generate a useable vaccine.
  • This example demonstrates a method for isolating WBC plasma membranes.
  • Frozen (-70°C) 38C13 murine B-lymphoma cells were quick-thawed at 37°C, suspended at 2 x 10 8 cells/mL in homogenization buffer (HB).
  • the composition of HB was 0.25 M sucrose, 10 mM Tris/HCl, 1 mM MgCl 2 , 1 mM KCl, phenylmethylsulfonyl fluoride (PMSF, 2 mM, final), trypsin-chymotrypsin inhibitor (200 ⁇ g/mL, final), DNase (10 ⁇ g/mL, final) and RNase (10 ⁇ g/mL, final), pH 7.3.
  • Experimental vaccine MB-RM-1A was formulated as follows: DMPC powder (1 g), 4 mL of the isolated 38C13 membranes (225 ⁇ g/mL IgM) in NSS and 160 ⁇ l of IL-2 (1.25 x 10 8 IU/mL) were placed in a 5 mL sterile glass vial, immediately vortexed, heated to 37 °C for 15 minutes in a water bath, then sonicated at 37 °C for 30 seconds in a bath sonicator. This suspension was subjected to three freeze/thaw cycles as follows:
  • the preparation was adjusted to a total volume of 5 mL with NSS and stored at -70 °C.
  • 4C5-Id is a non-specific antigen control
  • 38C13-Id is a vaccine consisting of soluble 38C13 immunoglobulin
  • 38C13-Id-KLH is a vaccine consisting of a conjugate between keyhole limpet hemocyanin and soluble 38C13
  • OV XIV-2 is a liposomal vaccine containing soluble 38C13-Id and IL-2.
  • a frozen (-70°C) pellet of 38C13 cells was quickly thawed at 37 °C in a water bath, then placed on ice. All subsequent treatments, unless otherwise specified were carried out on ice at 4 °C.
  • the pellet was washed with (5) volumes of ice cold PBS at 1K x g x 10 minutes.
  • the pellet was resuspended in ice-cold NSS containing 2 mM phenylmethylsulfonyl fluoride (PMSF), and 100 ⁇ g/mL each of DNAse and RNAse.
  • the cells were enucleated by emulsification through a 22 gauge needle (50 passes) and by using a hand held Dounce homogenizer (50 passes).
  • WBC plasma membranes were collected at the water/Nycodenz interface and washed with (7) volumes of NSS at 60K x g x 30 minutes.
  • the pelleted membranes were resuspended in NSS. A portion of these membranes was used to formulate MCFC9803 using the freeze/thaw method as described in Example 2.
  • the rest of the washed cell membranes were homogenized at 22K psi (15-20 passes) and used to formulate preparations MCFA9803 and MCFB9803.
  • FIG. 1 shows the effectiveness of MP vaccines produced according to the invention, and particularly shows survival data after formulation using three different methods for preparation.
  • the results show that the vaccinated mice survived a lethal B-cell lymphoma challenge.
  • the exemplary MP vaccines, MCFA9803 and MCFC9803 effectively protected 78% (7/9) and 90% (9/10), respectively, of the mice challenged with a lethal dose of 38C13 lymphoma cells.
  • Addition of IL-2 after lyophilization and during reconstitution was less effective (MCFB9803, 20% survival).
  • all the formulations offer some protection in this model of lymphoma.
  • This example demonstrates one alternate method of formulating a vaccine from isolated WBC membranes.
  • SUVs 0.5 mL at 200 mg/mL.
  • WBC membranes 0.5 mL
  • IL-2 (19 ⁇ l at 1.07 x 10 8 IU/mL) are combined and the mixture is lyophilized.
  • IL-2 Upon reconstitution with 0.5 mL distilled water 59% of the IL-2 is recovered of which 100% is incorporated in the membrane-proteoliposomes and 84% of the IgM is recovered of which 80% is incorporated in the membrane-proteoliposomes.
  • the mean membrane-proteoliposome size is 2.8 microns.
  • Freeze-fracture electron microscopy shown in Figure 2 reveals membrane-proteoliposomes with the characteristic ripple phase DMPC liposomes mixed with WBC membranes containing intramembranous particles.
  • the two distinct domains in one membrane-proteoliposome define the "patching" of WBC membranes with DMPC lipids.

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Claims (21)

  1. Vaccin pour le traitement d'une affection maligne des globules blancs, comprenant un liposome contenant une membrane plasmatique provenant d'un globule blanc malin du patient lui-meme.
  2. Vaccin suivant la revendication 1, dans lequel ledit globule blanc malin est une cellule de lymphome.
  3. Vaccin suivant la revendication 1, dans lequel le globule blanc malin est une cellule de leucémie.
  4. Vaccin suivant la revendication 1, dans lequel ledit globule blanc malin est une cellule de myélome.
  5. Liposome comprenant une membrane intégrale provenant d'un globule blanc malin, au moins un immunostimulateur et un lipide exogène.
  6. Liposome suivant la revendication 5, dans lequel ladite membrane contient au moins un constituant membranaire impliqué dans l'immunité.
  7. Liposome suivant la revendication 5 ou la revendication 6, comprenant au moins deux immunostimulateurs.
  8. Liposome suivant la revendication 6 ou la revendication 7, dans lequel ledit constituant est choisi dans le groupe consistant en un antigène spécifique d'une tumeur, un antigène du complexe majeur d'histocompatibilité et une molécule costimulatrice.
  9. Liposome suivant la revendication 8, dans lequel ladite molécule costimulatrice est la molécule B7.1, B7.2 ou ICAM-1.
  10. Liposome suivant l'une quelconque des revendications 5 à 9, dans lequel ledit immunostimulateur est une lymphokine.
  11. Liposome suivant la revendication 10, dans lequel ladite lymphokine est l'IL-2.
  12. Liposome suivant l'une quelconque des revendications 5 à 11, dans lequel ledit immunostimulateur est un interféron.
  13. Liposome suivant la revendication 12, dans lequel ledit interféron est le IFN-γ.
  14. Liposome suivant l'une quelconque des revendications 5 à 13, dans lequel ledit immunostimulateur est une cytokine.
  15. Liposome suivant la revendication 14, dans lequel ladite cytokine est le GM-CSF ou le M-CSF.
  16. Liposome suivant l'une quelconque des revendications 5 à 15, dans lequel ledit immunostimulateur est un adjuvant.
  17. Liposome suivant la revendication 16, dans lequel ledit adjuvant est choisi dans le groupe consistant en le monophosphoryl-lipide A, le lipide A et un conjugué lipidique de muramyl-dipeptide (MDP).
  18. Liposome suivant l'une quelconque des revendications 5 à 17, dans lequel ledit lipide est un phospholipide saturé ou insaturé ou un glycolipide.
  19. Liposome suivant la revendication 18, dans lequel ledit lipide est choisi dans le groupe consistant en la 1,2-dimyristoylphosphatidylcholine, 1a 1,2-dipalmitoylphosphatidylcholine, le 1,2-dimyristoylphosphatidyl-glycérol, le cholestérol et leurs associations.
  20. Liposome suivant l'une quelconque des revendications 5 à 19, dans lequel ledit lipide forme une membrane dans laquelle ladite membrane intégrale forme des plages.
  21. Liposome suivant l'une quelconque des revendications 5 à 20, dans lequel ledit lipide forme des plages dans ladite membrane intégrale.
EP99900822A 1998-01-16 1999-01-15 Vaccin specifique de patient contre les tumeurs malignes des leucocytes elabore a partir de proteoliposomes a membrane Expired - Lifetime EP1045698B1 (fr)

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US7170298P 1998-01-16 1998-01-16
US71702P 1998-01-16
PCT/US1999/000935 WO1999036085A1 (fr) 1998-01-16 1999-01-15 Vaccin specifique de patient contre les tumeurs malignes des leucocytes elabore a partir de proteoliposomes a membrane

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JP (1) JP2002509114A (fr)
AT (1) ATE328607T1 (fr)
AU (1) AU737330B2 (fr)
CA (1) CA2318557A1 (fr)
DE (1) DE69931749T2 (fr)
WO (1) WO1999036085A1 (fr)

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AUPQ755300A0 (en) * 2000-05-17 2000-06-08 Monash University Immune potentiating compositions
PE20020572A1 (es) * 2000-12-06 2002-07-31 Centro Inmunologia Molecular Preparaciones para potenciar la inmunogenicidad de antigenos poco inmunogenicos
EP2630968A1 (fr) * 2006-06-30 2013-08-28 Baylor Research Institute Cellules dendritiques générées au moyen de GM-CSF et de l'interféron alpha et chargées de cellules cancéreuses inhibées et thermo-traitées
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US20020155135A1 (en) 2002-10-24
AU2031899A (en) 1999-08-02
DE69931749D1 (de) 2006-07-20
EP1045698A1 (fr) 2000-10-25
US6207170B1 (en) 2001-03-27
ATE328607T1 (de) 2006-06-15
DE69931749T2 (de) 2007-05-31
WO1999036085A1 (fr) 1999-07-22
CA2318557A1 (fr) 1999-07-22
US20010012517A1 (en) 2001-08-09
AU737330B2 (en) 2001-08-16

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